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Maglione M, Maher AR, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. (Comparative Effectiveness Reviews, No. 43.)

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Off-Label Use of Atypical Antipsychotics: An Update [Internet].

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Summary and Discussion

We conducted an extensive literature search, data abstraction, and meta-analyses, whenever possible, to assess the efficacy, comparative effectiveness, and safety of atypical antipsychotics for off-label indications. Since the submission of our original comparative effectiveness review (CER)in 2006, many new high-quality controlled trials have been published; we were able to add many to our prior quantitative analyses and conduct additional analyses on new conditions and adverse events. In this chapter, we describe the limitations of our review and meta-analyses and then present our conclusions. We also discuss the implications of our findings for future research.

Limitations. Our literature search procedures were extensive and included canvassing experts from academia and industry regarding studies we may have missed. However, the possibility of publication bias still exists. For the most part, our assessment did not yield any evidence of unexplained heterogeneity. Two exceptions include one outcome for depression and the Y-BOCS “percent of participants responded” outcome used in our obsessive-compulsive disorder (OCD) meta-analysis. In our analysis of atypicals as augmentation in treatment of major depressive disorder (MDD), possible publication bias appeared in studies reporting the percent of participants remitted according to the Montgomery-Asberg Depression Rating Scale (MADRS). We conducted additional efficacy meta-analyses using Hamilton Depression Rating Scale (HAM-D) outcomes; efficacy results were similar, but no heterogeneity was detected. Thus, our confidence that some atypicals are efficacious as augmentation of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepineprhine reuptake inhibitors (SNRIs) for depression remains despite evidence of possible publication bias. Heterogeneity was also evident in studies assessing the efficacy of atypicals for OCD. This heterogeneity was likely due to patient enrollment criteria; studies used different definitions of “refractory” and “treatment resistant.” Another published meta-analysis of atypicals for OCD192 found similar efficacy results but no heterogeneity according to statistical tests.

Furthermore, when we reviewed the recent meta-analysis assessing death and the use of these drugs in persons with dementia, we learned of the existence of some manufacturer-supported trials, the published results of which we searched for and were not able to find, despite extensive computerized searches and requests to the manufacturers (we have since learned the results were not published). It is possible that other such unpublished trial results exist for the other conditions included in our report. In addition, we excluded non-English language studies. Thus, we assume that publication bias may occur for all conditions, resulting in an overestimation of efficacy of these drugs and conditions.

An important limitation common to systematic reviews is the quality of the original studies included. In order to measure the quality of clinical trials we used the Jadad scale.17 As empirical evidence regarding other study characteristics and their relationship to bias is lacking, we did not attempt to use other criteria. However, other aspects of the design and execution of a trial may be related to bias, but we do not yet have good measures of these elements. In our 2006 CER on off-label use of atypicals, we conducted a sensitivity analysis on the relationship between trial quality and effect size; the better quality trials reported an effect size 25 percent smaller than did lower quality trials. This finding increases the likelihood that a synthesis of results of all studies—whether narrative or quantitative—may produce inflated estimates of efficacy. As stated above, the higher general quality of the dementia and depression augmentation studies led to a greater strength of evidence rating for those uses. Another factor contributing to our conclusions is the degree to which the available evidence comes from manufacturer-supported studies. In studies of other drugs and in studies of atypical antipsychotic drugs in particular, there is evidence that sponsorship by the manufacturer is more likely to yield results favorable to the manufacturer's product. In some cases this has been related to design or reporting methods that intentionally favor the manufacturer's product. Thus, to the extent that all or almost all of the available evidence supporting drug/indication came from the manufacturer, we downgraded our confidence in the conclusion. The existence of Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD), which was federally sponsored and reported results consistent with the manufacturer supported studies, substantially increases our confidence regarding the studied atypical antipsychotics for elderly patients with dementia.

We could come to very few conclusions regarding dosage. Most trials used flexible dosing, so patients were on a wide range of doses.

Applicability of research to the larger treatment population is important in interpreting the results of the included studies. The participation rate, the intended target population, representativeness of the setting, and representativeness of the individuals must be known to assess applicability. Such data were reported unevenly in the studies we reviewed. The dementia trials were most often conducted in nursing homes, hospitals, or assisted living facilities. According to our review on utilization patterns, these settings represent where atypicals are most often used in the elderly. Studies for other conditions were not particularly representative. For example, three of the four trials for Attention-Deficit Hyperactivity Disorder (ADHD) were conducted in children with severe co-occurring conditions, such as bipolar disorder or mental retardation.

In the studies of atypicals as augmentation for SSRI or SNRI patients with MDD, it was often unclear whether patients were simultaneously undergoing psychotherapy. One trial165 specifically stated that subjects were prohibited from initiating such therapy during the trial, but other reports were unclear on the issue. Thus, it is unclear whether treatment over and above the medication influenced the study results. As many depression patients are treated in primary care, it is important to note that subjects in the depression trials were recruited from both primary care and mental health centers.

We found only one controlled trial of atypicals for treatment of insomnia. Among observational studies only one small one188 included patients with insomnia as primary diagnosis. Others included patients with Parkinson's disease, MDD, polysubstance abuse withdrawal symptoms, and tamoxifen induced insomnia. Thus, the results of these studies should not be applied to the general population.

Conclusions. Tables 30 and 31 present the most clinically relevant findings. It is important to note that we found no trials, large observational studies, or utilization studies of the three newest atypicals (asenapine, iloperidone, and paliperidone) for off-label uses. Table 30 is organized as follows: First, all conditions dealt with in our original CER, in alphabetical order; second, all the new off-label indications in alphabetical order.

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Table 30

Summary update: efficacy of atypical antipsychotics for off-label use.

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Table 31

Summary update: safety of atypical antipsychotics for off-label use.

Future Research

The overarching finding of this review is that although atypical antipsychotic medications are being used for a large number of off-label uses, we were able to find moderate to strong evidence to support efficacy for only a few of the drugs and only a few of the off-label uses. Most of the evidence is concentrated in the drugs risperidone, olanzapine, and quetiapine, and the conditions dementia, depression, and obsessive-compulsive disorder. For the newly approved atypicals (asenapine, iloperidone, and paliperidone), we found no clinical trials assessing their use for any off-label condition, and for some off-label uses, we found no or only a small number of trials. Head-to-head comparisons of atypical antipsychotic drugs for off-label uses are few, and evidence from placebo-controlled trials for off-label uses suggests that efficacy differs between drugs, meaning that the assumption of a “class effect” for atypical antipsychotics may be unwarranted. This means that each drug is going to require its own evaluation of efficacy for each off-label indication, which is a large task; and then drugs demonstrated to be efficacious will need to be tested head-to-head in trials of comparative effectiveness.

With respect to use in individual off-label conditions, we offer the following thoughts.

ADHD. We found three placebo-controlled trials and one active-control trial. Two of these studied risperidone and two studied aripiprazole. Though these did find some efficacy for ADHD, the trials utilized differing outcome measures and the patient populations differed in severity of illness and comorbid conditions. For these reasons, the trials could not be pooled and overall efficacy in ADHD still needs to be established for each medication. Future research should utilize one standard measure of ADHD in order for them to be compared. In addition, we learned from utilization studies that other atypical antipsychotic medications, such as quetiapine and olanzapine are being used frequently for ADHD. As we found no trials of their efficacy, future research should include studies of these medications.

Anxiety. Though there were many placebo-controlled trials of atypicals for anxiety symptoms, only three were clinically similar enough to pool. These trials used quetiapine for generalized anxiety disorder. There were mixed reports of efficacy for the other atypicals and there were no studies of anxiety treatment with aripiprazole. Future research needs to include additional studies of the various atypical agents. As the Hamilton Anxiety Rating Scale (HAM-A) was the most commonly used measure, if these future trials utilized the HAM-A, it will be possible to compare across trials.

Dementia. Given the concern over serious adverse events such as mortality, knowledge of the efficacy of atypical antipsychotics in the demented elderly is of paramount importance. We found evidence that aripiprazole, olanzapine and risperidone were superior to placebo in treating agitation, psychosis, and behavioral symptoms. We found no trials of ziprasidone in dementia. An assessment of the net efficacy compared with the side effect burden would be useful in future studies.

Depression. There were enough trials of quetiapine and risperidone to pool to show efficacy when used an augmentation agent. Olanzapine augmentation was shown to be superior to placebo but there were only two trials. There was only one placebo-controlled trial of ziprasidone in depression. Though it was found to be superior, further studies to confirm this finding are required.

Eating Disorders. As weight gain is a common side effect experienced during treatment of other conditions with olanzapine, the assumption has been that this side effect could be exploited for therapeutic benefit as a treatment for eating disorders. Though commonly used clinically, the four trials of olanzapine in eating disorders found that it led to no statistically significant difference in body mass index. Mechanistic studies to explain differences in those with eating disorders from those with other psychiatric conditions may elucidate why weight gain occurs in some populations but not others.

Insomnia. Insomnia is another condition where the side effects of atypical antipsychotics are exploited for treatment. Atypicals, particularly olanzapine and quetiapine, are commonly sedating. Clinical trials are needed to rigorously test the conclusions from observational studies that olanzapine and quetiapine are useful in promoting sleep quality and sleep onset. Placebo controlled trials confirming their efficacy are necessary before reaching any conclusions.

OCD. Several trials reported the efficacy of quetiapine as an augmentation agent in OCD along with a few of risperidone. Further studies of olanzapine and aripiprazole are required in order to assess their efficacy. In addition, further trials comparing the atypical antipsychotic agents to the current standards of treatment would be helpful in order to know at which point of treatment failure there benefit is greatest. For example, one trial found that quetiapine had greater efficacy in reducing the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score than clomipramine, though clomipramine is currently a more widely recommended treatment for resistant OCD. If further trials confirmed this result, atypical antipsychotics could be placed higher on an algorithm for recommended treatment.

Personality Disorders. Personality disorders have remained a difficult area for clinicians, leading to continued exploration for successful treatments. Unfortunately, our ability to reach strong conclusions is hindered by the heterogeneity of the trials reviewed. Future research should have standard outcomes so that results across trials can be compared. In our review, olanzapine and risperidone had mixed results, and quetiapine and aripiprazole were found to have some efficacy while ziprasidone did not. However, there were too few trials to allow for clinicians to predict the effect of a particular agent for a particular patient. Before reaching conclusions regarding clinical use further research, with comparable outcomes, is necessary.

Post-Traumatic Stress Disorder. Some studies found efficacy for risperidone, olanzapine and quetiapine for the symptoms of post-traumatic stress disorder (PTSD). An issue in PTSD is the question of whether the results are affected by gender. Our review found that the atypicals showed efficacy in male combat veterans but not female victims of civilian trauma. Whether this signifies that efficacy differs by gender or rather that combat trauma is more amenable to treatment with atypicals than civilian trauma requires further research to elucidate.

Substance Abuse. Trials of atypical antipsychotic treatment for substance abuse did not find them superior to placebo on substance use measures. Future research is needed to establish a role, if any, in the use of atypical antipsychotic drugs in the treatment of substance abuse.

Tourette's Syndrome. Other than efficacy demonstrated with risperidone, there is only one placebo-controlled trial of another atypical antipsychotic, ziprasidone, as a treatment for Tourette's syndrome. Additional trials are needed before any conclusions can be reached regarding the other atypicals.

In addition to the research recommended above, there is almost no evidence about how treatment efficacy may vary within populations, including variations due to gender, race, ethnicity, or other comorbidities. In addition, existing evidence about the effect of baseline severity of disease is too heterogeneous to allow us to draw conclusions. In future research, standardized measures of disease severity might allow for greater knowledge of the patient populations who would benefit from treatment with atypical agents.

Regarding adverse effects of the atypical antipsychotics, existing evidence varies by drug and by description of the adverse event. It would facilitate assessments if future studies contained a standardized list of assessed side effects. As many trials report only those effects observed, we are unable to compare between trials for many of the side effects.

Two of the adverse events deserve further comment, because they potentially differ from the perception of clinical psychiatrists. In four studies including 1,387 nonelderly patients, aripiprazole was associated with weight gain, and in seven studies including 2,566 nonelderly patients quetiapine was associated with extrapyramidal symptoms. We consider these findings to be a signal deserving of further investigation.

Another area where clinical guidance is needed is in the dosages required to achieve effects in off-label indications. The dosages used off-label varied from those used for on-label indications. There were a few trials that compared dosage efficacy, but most used flexible dosing. Thus, a dosage comparison across trials was generally not possible. More research examining differing dosages within the same population is required in order to guide clinicians in the appropriate doses to prescribe. A similar issue is that of treatment length. More research reporting responses at various time points would be helpful in determining how long treatment is required. Given the risk of side effects when using these agents, clinicians need to know when a result is expected to prevent continuing an ineffective agent, unnecessarily.

Newer agents, such as asenapine, iloperidone and paliperidone cannot be assumed to have efficacy and harms similar to the older atypical antipsychotics, since the evidence does not support that there is a general “class effect” in terms of either efficacy or harm for most off-label indications. Trials assessing the newer agents' efficacy and safety are necessary in each of the treatment areas if they are to be prescribed for off-label use.

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